Obesity and obesity-related disorders, such as type 2 diabetes, hypertension, and cardiovascular disease, have increased dramatically in Western countries, particularly the United States during the past decades. The reasons for this increase are likely to be multifactorial; one of the suggested emerging causes being the accelerated exposure to obesity or diabetes-inducing chemicals (obesogens or diabetogens). However, out of the tens of thousands of industrial chemicals that humans are exposed to, very few have been tested for obesogenic or diabetogenic capacity, mostly due to the limited availability of appropriate screening models. We here propose to develop zebrafish-based screens to identify obesogens and diabetogens and determine dose-response effects and critical windows of exposure. The aims are 1) To develop the zebrafish obesogen screen based on lipid binding fluorochromes 2) To establish the zebrafish diabetogen screen based on transgenic zebrafish, and 3) To characterize the mechanisms of action of obesogens and diabetogens in zebrafish. The expected outcomes of this project are medium to high throughput models for obesogen and diabetogen screening, taking advantage of the external (ex-utero), rapid and transparent embryonic development as well as cost efficiency of zebrafish screens. This is in line with the vision of the National Toxicology Program (NTP) as described in its 21st Century Roadmap to Achieve the NTP Vision in refining traditional toxicology assays, developing rapid, mechanism-based predictive screens for environmentally induced diseases (US National Toxicology Roadmap A national toxicology program for the 21st century; ://ntp.niehs.nih.gov/files/ NTPrdmp.pdf). We will identify obesogens and diabetogens, critical windows of exposure and effect doses. By incorporating of our generated results and models into other chemical screening activities in the US, performed by NTP and EPA, and through collaborations with other initiatives taken in the field of chemical safety, we will participate in the large screening effort to prioritize chemicals for further risk assessment. The ultimate impact of this project is o contribute to protection of the population from exposure to obesogens and diabetogens during critical periods in life, which is in line with the overall NIH mission to protect human health through prevention of disease, to protect the developing fetus, and to increase the knowledge of biological effects of environmental contaminants (NIH Mission; ://www.nih.gov/about/mission.htm). In addition, this proposal explores the zebrafish model as a tool for toxicity screening, which is supported by NIH's strong advocacy of zebrafish and other animal model systems for biomedical and behavior research (Henken DB, Rasooly RS, Javois L, Hewitt AT. 2004 National Institutes of Health Trans-NIH Zebrafish Coordinating Committee. The National Institutes of Health and the growth of the zebrafish as an experimental model organism. Zebrafish. 1(2):105-10). ! PUBLIC HEALTH RELEVANCE: Obesity and obesity-related disorders, such as type 2 diabetes, hypertension, and cardiovascular disease, have increased dramatically in Western countries, particularly the United States during the past decades. One emerging cause of the increase might be that we are exposed to industrial chemicals that promote obesity. However, out of the tens of thousands of chemicals that we are exposed to, very few have been tested for their capacity to cause obesity or diabetes, largely due to the lack of models to screen these compounds. In this project, we will produce a screening model to identify chemicals that induce obesity and diabetes. The screening model is based upon zebrafish, which, despite their apparent difference to humans, have similar biological ways of making and storing fat, and producing insulin. These models will be used to screen chemicals and to predict the risk of chemical exposure to humans. !